ABSTRACT Children with sickle cell disease (SCD) experience widespread cognitive deficits along with numerous other medical consequences including stroke, silent cerebral infarction (SCI), acute chest syndrome, pulmonary hypertension, chronic kidney disease, and premature death. Molecular changes within the sickled cell greatly reduces the oxygen-carrying capacity of the blood, but understanding of the pathophysiology of cerebrovascular disease such as stroke and SCI is inadequate. Therefore, the specific mechanisms by which cognitive deficits occur are not yet fully understood. The cognitive deficits experienced by children with SCD are associated with impairments in daily functioning and reduced education attainment, making cognition a critical target for treatment and intervention. Thus, understanding how cognitive deficits are related to poor white matter in children with SCD with and without SCI is a critical next step in efforts to intervene and remediate cognitive deficits. Because children with SCD experience widespread white matter abnormalities, we suggest that characterizing their brain organization as a structural connectome may help to explain why changes in axon fiber microstructure (e.g., demyelination or loss of axons) in diffuse locations along a fiber pathway may lead to the same cognitive deficits in different children. As this is the first study to assess structural connectomes using diffusion MRI in children with SCD, we begin with the broad aim to determine whether children with SCD have impaired global structural connectivity efficiency in comparison to controls. We will next determine whether children with SCD and SCI and children with SCD without SCI have differences in network efficiency calculated using graph theory analyses. Additionally, we will investigate rich club organization, which is a set of highly connected and interconnected regions and determine whether there are differences between children with SCD and controls and investigate whether there is preferential rich club disruption in children with SCD and SCI. We will examine whether these graph metrics correlate with cognition in SCD with and without SCI. Finally, we will assess Montelukast, a targeted intervention, and whether Montelukast provides improvements in oxygen availability and thus improves global structural connectivity efficiency and rich club organization in children with sleep-disordered breathing, a common medical complication associated with SCD. The goal of this proposal is to gain a more complex understanding of the global efficiency and rich club organization of the structural connectome, determine associations with cognitive deficits, and whether efficiency can be improved and cognitive deficits be ameliorated by intervention. The findings will have important implications for functional outcomes for children with SCD and will provide information that could influence the development of future treatment options tailored to the specific cognitive and clinical needs of this population.